(1) Field of the Invention
The present invention generally relates to retrovirus inhibitors. More specifically, the invention is directed to the inhibition of HIV-1 with fragments of INI1/hSNF5 and with compounds that inhibit the production of INI1/hSNF5.
(2) Description of the Related Art
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PCT Publication WO 88/09810.
PCT Publication WO 89/10134.
PCT Publication WO 90/11364.
PCT Publication WO 88/04300.
U.S. Pat. No. 5,093,246.
Although multi-drug therapy is an effective anti-HIV-1 treatment, viral relapses occur in at least half of the patients due to incomplete adherence to drug regimen, resulting in the emergence of drug resistant variants thus necessitating the development of new efficacious anti-HIV-1 therapeutic agents. HIV-1 proteins such as integrase (often abbreviated IN) and the cellular proteins implicated in viral replication are attractive new targets (Pani and Marongiu, 2000; Pommier and Neamanti, 1999; Mathe and Nair, 1999). Integrase catalyses integration of HIV-1 DNA into the host genome, an essential step in HIV-1 replication (Assante-Appiah and Skalka, 1997; Brown, 1990; Desrosiers, 1999). HIV-1 integrase consists of an N-terminal Zn-finger domain, a catalytic core domain with a conserved D, D (35) E motif, and a C-terminal domain. In vivo studies using molecular clones of HIV-1 have demonstrated that integrase mutations have pleiotropic effects, blocking other steps of viral replication in addition to integration (Assante-Appiah and Skalka, 1997; Brown, 1990; Desrosiers, 1999, Brown, 1997; Engleman et al., 1995; Masuda et al., 1995; Wu et al., 1999; Leavitt et al., 1996; Nakamura et al., 1997). Understanding the mechanism of these pleiotropic effects may lead to the development of antiviral drugs that affect multiple steps of HIV-1 life cycle, by simply targeting IN.
INI1/hSNF5, isolated via a yeast two-hybrid screen (Kalpana et al., 1994; Morozov et al., 1998), is the only known host protein that directly interacts with HUV-1 integrase (Leavitt et al., 1996; Nakamura et al., 1997). INI1/hSNF5 is a tumour suppressor and a core component of the SWI/SNF complex involved in chromatin remodelling (Versteege et al., 1998; Biegel et al., 1999; Wang et al., 1996; Kingston and Narlikar, 1999). It has three highly conserved domains, two of which are imperfect repeats (Rpt1 and Rpt2). HIV-1 integrase specifically binds to Rpt1 but not Rpt2 of INI1/hSNF5 despite their similarity (Morozov et al., 1998).